The exit from naive pluripotency: a platform for the study of enhancer mechanistics

Multicellular life depends on the ability to activate and repress genes in a highly context-specific manner. With each cell state transition, a new transcriptional profile is established. As non-coding DNA elements, enhancers mediate their regulatory potential through the effectors they recruit. While ultimately instructed by the underlying DNA sequence, enhancer activity depends on several factors, such as transcription factor availability, chromatin state, and promoter proximity, all of which are dynamically regulated within the cell. Even when we understand the regulation of one enhancer, its genomic impact is dependent on its integration within the regulatory landscape. Thus, a full picture of enhancer dynamics can only be painted through broad, but controlled, approaches that integrate investigations into multiple levels of gene regulatory mechanisms. In this review, we will present the exit of naive pluripotency as a prime setting to do just that and contextualize how its contemporary use has been, and could be, used to reveal the intricacies of enhancer mechanistics.